Detecting Pedigree Relationship Errors

Part of the Methods in Molecular Biology book series (MIMB, volume 1666)


Pedigree relationship errors often occur in family data collected for genetic studies, and unidentified errors can lead to either increased false positives or decreased power in both linkage and association analyses. Here, we review several allele sharing as well as likelihood-based statistics that were proposed to efficiently extract genealogical information from available genome-wide marker data, and the software package PREST that implements these methods. We provide the detailed analytical steps involved using two application examples, and we discuss various practical issues, including result interpretation.

Key words

Pedigree error Relationship estimation IBD IBS IIS Allele sharing Likelihood Hidden Markov model EM algorithm Software PREST PREST-plus Multiple hypothesis testing Simulation Linkage Association Robustness 


  1. 1.
    Boehnke M, Cox NJ (1997) Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 61(2):423–429CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Voight BF, Pritchard JK (2005) Confounding from cryptic relatedness in case-control association studies. PLoS Genet 1(3):e32CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Thornton T, McPeek MS (2010) Roadtrips: case-control association testing with partially or completely unknown population and pedigree structure. Am J Hum Genet 86(2):172–184CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Goring HH, Ott J (1997) Relationship estimation in affected sib pair analysis of late-onset diseases. Eur J Hum Genet 5(2):69–77PubMedGoogle Scholar
  5. 5.
    O'Connell JR, Weeks DE (1998) Pedcheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63(1):259–266CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ehm M, Wagner M (1998) A test statistic to detect errors in sib-pair relationships. Am J Hum Genet 62(1):181–188CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    McPeek MS, Sun L (2000) Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet 66(3):1076–1094CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2001) Grr: graphical representation of relationship errors. Bioinformatics 17(8):742–743CrossRefPubMedGoogle Scholar
  9. 9.
    Sieberts SK, Wijsman EM, Thompson EA (2002) Relationship inference from trios of individuals, in the presence of typing error. Am J Hum Genet 70(1):170–180CrossRefPubMedGoogle Scholar
  10. 10.
    Sun L, Wilder K, McPeek MS (2002) Enhanced pedigree error detection. Hum Hered 54(2):99–110CrossRefPubMedGoogle Scholar
  11. 11.
    Rabiner L (1989) A tutorial on hidden Markov models and selected applications in speech recognition. Proc IEEE 77(2):257–286CrossRefGoogle Scholar
  12. 12.
    Sun L (2001) Two statistical problems in human genetics. University of Chicago, PhD thesisGoogle Scholar
  13. 13.
    Thompson EA (1975) The estimation of pairwise relationships. Ann Hum Genet 39(2):173–188CrossRefPubMedGoogle Scholar
  14. 14.
    Thompson EA (1986) Pedigree analysis in human genetics. The Johns Hopkins University Press, BaltimoreGoogle Scholar
  15. 15.
    Dimitromanolakis A, Paterson AD, Sun L (2009) Accurate IBD inference identifies cryptic relatedness in 9 HapMap populations. Abstract #1768 presented at the annual meeting of the American Society of Human GeneticsGoogle Scholar
  16. 16.
    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) Plink: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Statist Soc Ser B 57:289–300Google Scholar
  18. 18.
    Craiu RV, Sun L (2008) Choosing the lesser evil: trade-o_ between false discovery rate and non-discovery rate. Stat Sin 18:861–879Google Scholar
  19. 19.
    Sun L, Craiu RV, Paterson AD, Bull SB (2006) Stratified false discovery control for large-scale hypothesis testing with application to genome-wide association studies. Genet Epidemiol 30:519–530CrossRefPubMedGoogle Scholar
  20. 20.
    Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM (2010) Robust relationship inference in genome-wide association studies. Bioinformatics 56(22):2867–2873CrossRefGoogle Scholar
  21. 21.
    Chen WM, Manichaikul A, Rich SS (2016) KING 2.0: relationship inference and integrated analysis in one million samples. Abstract #365T presented at the American Society of Human Genetics annual meetingGoogle Scholar
  22. 22.
    Begleiter H, Reich T, Nurnberger JJ, Li TK, Conneally PM, Edenberg H, Crowe R, Kuperman S, Schuckit M, Bloom F, Hesselbrock V, Porjesz B, Cloninger CR, Rice J, Goate A (1999) Description of the genetic analysis workshop 11 collaborative study on the genetics of alcoholism. Genet Epidemiol 17(Suppl 1):S25–S30CrossRefPubMedGoogle Scholar
  23. 23.
    Antoni G, Morange P, Luo Y, Saut N, Burgos G, Heath S, Germain M, Biron-Andreani C, Schved J, Pernod G, Galan P, Zelenika D, Alessi M, Drouet L, Visvikis-Siest S, Wells P, Lathrop M, Emmerich J, Tregouet D, Gagnon F (2010) A multi-stage multi-design strategy provides strong evidence that the bai3 locus is associated with early-onset venous thromboembolism. J Thromb Haemost 8:2671–2679. doi: 10.1111/j.1538-7836.2010.04092.x CrossRefPubMedGoogle Scholar
  24. 24.
    Epstein MP, Duren WL, Boehnke M (2000) improved inference of relationship for pairs of individuals. Am J Hum Genet 67(5):1219–1231CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    McPeek MS (2002) Inference on pedigree structure from genome screen data. Stat Sin 12:311–335Google Scholar
  26. 26.
    Sun L, Abney M, McPeek MS (2001) Detection of mis-specified relationships in inbred and outbred pedigrees. Genet Epidemiol 21(Suppl 1):S36–S41CrossRefPubMedGoogle Scholar
  27. 27.
    Broman KW, Weber JL (1998) Estimation of pairwise relationships in the presence of genotyping errors. Am J Hum Genet 63(5):1563–1564CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ray A, Weeks DE (2008) Relationship uncertainty linkage statistics (RULS): affected relative pair statistics that model relationship uncertainty. Genet Epidemiol 32(4):313–324CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.Department of Statistical Sciences, Faculty of Arts and ScienceUniversity of TorontoTorontoCanada
  2. 2.Division of Biostatistics, Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada

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